The background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
ATP-binding cassette transporters (ABC transporters) are members of a protein superfamily that is one of the largest and oldest families with representatives in all extant phyla from prokaryotes to humans. ABC transporters are transmembrane proteins that utilize the energy of adenosine triphosphate (ATP) binding and hydrolysis to carry out certain biological processes including translocation of various substrates across membranes and non-transport-related processes such as translation of RNA and DNA repair. They transport a wide variety of substrates across extra- and intracellular membranes, including metabolic products, lipids and sterols, and drugs. Proteins are classified as ABC transporters based on the sequence and organization of their ATP-binding cassette (ABC) domain(s). ABC transporters are involved in tumor resistance, cystic fibrosis and a range of other inherited human diseases along with both prokaryotic and eukaryotic (including human) development of resistance to multiple drugs.
ABC transporters utilize the energy of ATP binding and hydrolysis to transport various substrates across cellular membranes. They broadly function in different ways—firstly as importers, they mediate the uptake of nutrients into the cells, secondly as exporters or effluxers, when they function as pumps that extrude toxins and drugs out of the cell and lastly do not function as transporters, but are rather involved in translation and DNA repair processes. P-glycoprotein (P-gp) is one of the important proteins of the ABC (ATP—binding cassette) superfamily. This protein can export an astonishing variety of amphipathic drugs, natural products, and peptides from mammalian cells, powered by the energy of ATP hydrolysis.
Noninvasive, nuclear imaging techniques can be used to obtain basic and diagnostic information about the physiology and biochemistry of living subjects, including experimental animals, normal humans and patients. These techniques rely on the use of imaging instruments that can detect radiation emitted from radiotracers administered to living subjects. The information obtained can be reconstructed to provide planar and tomographic images which reveal the distribution and/or concentration of the radiotracer as a function of time.
Diagnostic techniques in nuclear medicine use radioactive tracers which emit gamma rays from within the body. These tracers are generally short-lived isotopes linked to chemical compounds which facilitate investigations of specific physiological processes. They can be given by injection, inhalation or orally. The first types are where single photons are detected by a gamma camera which can view organs from many different angles. The camera builds up an image from the points from which radiation is emitted; this image is enhanced by a computer and viewed by a physician on a monitor for indications of abnormal conditions. A more recent development is Positron Emission Tomography (PET) which is a more precise and sophisticated technique using isotopes produced in a cyclotron. A positron-emitting radionuclide is introduced, usually by injection, and accumulates in the target tissue. As it decays it emits a positron, which promptly combines with a nearby electron resulting in the simultaneous emission of two identifiable gamma rays in opposite directions. These are detected by a PET camera and give very precise indication of their origin. PET's most important clinical role is in oncology, diseases of the central nervous system, etc. The most commonly used positron-emitting radionuclides are 15O, 13N, 11C and 18F, which are usually accelerator-produced and have a half life of 2, 10, 20 and 110 minutes, respectively. The most widely used gamma-emitting radionuclides are 18F, 99mTc, 201TI and 123I.
Numerous formulations and compounds with fluorine-18 as the radio isotope are known in the prior art, since it has proven to be the most accurate non-invasive method of detecting and evaluating most cancers. Gamma imaging provides a view of the position and concentration of the radioisotope within the body. Organ malfunction can be indicated if the isotope is either partially taken up in the organ (cold spot), or taken up in excess (hot spot). If a series of images is taken over a period of time, an unusual pattern or rate of isotope movement could indicate malfunction in the organ.
While there has been vast improvement in diagnostics techniques, it has also been observed that many/certain drugs tend to become ineffective and lose their efficacy after certain time. This has been variously attributed to multi drug resistance (MDR). It affects patients with various ailments including a variety of blood cancers and solid tumors, such as breast, ovarian, lung, and gastrointestinal tract cancers. Drug resistance associated with drug efflux, mediated by ATP transporters such as Pgp, BCRP and MRP1 is reported in mammalian cells.
Pgp, BCRP and MRP1 are important ATP Binding Cassette transporter widely expressed in the body and play a crucial role in Multidrug Resistance (MDR). P-glycoprotein is the best-studied efflux pump and as such has offered important insights into the mechanism of bacterial pumps. For these reasons P-gp represent a new potential marker useful in monitoring and diagnosis of resistant tumors. In the last decade several efforts have been addressed in searching compounds able to interact with the pump with different mechanism. These compounds could be radiolabeled with 11C and 18F and employed as P-gp tracer by PET techniques. Failure of chemotherapy due to MDR1/P-gp mediated resistance is a well-characterized biomarker of a more aggressive and malignant phenotype in breast cancer pathology. Currently there are no methods or tests available to assess or detect the cause of multi drug resistance in patients.
U.S. Pat. No. 7,989,630 discloses a method of using a substrate for P-glycoprotein where the substrate carries 18F(CH2)2 {[18]F fluoroethyl} as a Positron Emission Tomography (PET) radio tracer for detecting cancer such as breast cancer.
Kazunori Kawamura, et al. “Synthesis and in vivo evaluation of 18F-fluoroethyl F120918 and XR9576 as positron emission tomography probes for assessing the function of drug efflux transporters” Bioorganic & Medicinal Chemistry, 19(2), pp 861-870 (2011) alludes to the possibility of the [18F]-Tariquidar being a substrate for drug efflux transporters. Tariquidar is Pgp inhibiter currently under clinical trials which non-competitively binds to the p-glycoprotein transporter, thereby inhibiting transmembrane efflux of anticancer drugs.
Thomas Wanek, et al. , “A comparative small-animal PET evaluation of [11C]tariquidar, [11C]elacridar and (R)-[11C]verapamil for detection of P-glycoprotein-expressing murine breast cancer” European Journal of Nuclear Medicine and Molecular Imaging, 39(1), pp 149-159 (2012) discloses a method of using radio-labeled [11C]tariquidar in Positron Emission Tomography (PET) evaluation for detecting P-glycoprotein-expressing murine breast cancer.
A number of PET and SPECT (single photon emission tomography) tracers have been developed to demonstrate the presence of P-gp in tissue, but none of these tracers are applied to drug development or currently used as routine clinical diagnostic tool. Although these imaging tools have their utility, their sensitivity and therefore their scope for research purposes is limited. At most, a 2-3 fold increase of uptake in the P-gp expressing tissue (brain/tumour) is observed at the assumed 100% inhibition dose. This means that if small changes (e.g. <20%) in P-gp functionality suffice for co-treatment in for example tumour therapy, current imaging tools may not be sensitive enough to establish the change in P-gp functionality with sufficient confidence and may therefore not be suitable for establishing the required dose of P-gp inhibitor or competitive substrate. The P-gp transport system is complex and poorly understood in man in vivo and highly sensitive radiotracers which could be used in vivo would be especially beneficial in elucidating P-gp's role in drug and toxin resistance, immunity, apoptosis or cell differentiation.
Several ligands have been developed and radiolabeled to image P-gp (vepamil, tariquidar, elacridar, N-desmethyloperamide) and today [11C]verapamil is the only one used in clinical studies. Tariquidar is a P-gp inhibitor currently under clinical trials.
The radiotracers have been limited in clinical application because of different in vivo behavior, with respect to preliminary in vitro studies, by low uptake and selectivity and presence of radio metabolites.
There is thus a need in the art to develop novel anthralinic acid derivatives which are capable of being used as radiotracers in PET imaging, as well as targeted radionuclide therapy of one or more conditions that may be regulated or normalized via inhibition of ATP transporters selected from P-gp, BCRP and MRP1. Further, it would be more beneficial if such new compounds can also be used as substrates for these ABC transporters to study in-vitro and in-vivo overexpression of ATP transporters and diagnosis of MDR.
The present invention satisfies the above needs and overcomes the deficiencies generally found in the prior art.